SUMMARY: The Food and Drug Administration (FDA) is issuing a final
rule establishing new warning statements and other labeling information
for all over-the-counter (OTC) vaginal contraceptive drug products
(also known as spermicides, hereinafter referred to as vaginal
contraceptives or vaginal contraceptives/spermicides) containing
nonoxynol 9 (N9). These warning statements will advise consumers that
vaginal contraceptives/spermicides containing N9 do not protect against
infection from the human immunodeficiency virus (HIV), the virus that
causes acquired immunodeficiency syndrome (AIDS), or against getting
other sexually transmitted diseases (STDs). The warnings and labeling
information will also advise consumers that use of vaginal
contraceptives and spermicides containing N9 can irritate the vagina
and rectum and may increase the risk of getting the AIDS virus (HIV)
from an infected partner. This final rule is part of FDA's ongoing
review of OTC drug products. FDA is issuing this final rule after
considering public comments on its proposed regulation, and all
relevant data and information on N9 that have come to our attention.

DATES: Effective Date: This rule is effective June 19, 2008.
Compliance Date: The compliance date for all products subject to
this final rule, including products with annual sales less than
$25,000, is June 19, 2008.

I. Background
II. Comments on the Proposed Rule and FDA's Responses
A. Should N9 Remain Available as an Active Ingredient in OTC
Vaginal Contraceptive Drug Products?
B. What Issues Were Raised by Comments That Did Not Support the
Proposed Warning Statements?
1. Will Warning Labels Be Seen, Understood, or Followed?
2. Are the Warnings Supported by the Scientific Literature?
3. Is FDA Required To Prove Actual Causation To Justify the
Warnings?
C. Should Women Ask a Doctor Before Using N9 Products?
D. Where Will the Warnings Appear in the Labeling?
E. Where Will the Condom Usage Statement Appear in the Labeling?
F. What Were the Comments on Condoms, Sexual Lubricants, and
Barrier Methods?
1. Do Warnings Apply to Condoms and Sexual Lubricants?
2. Are Condoms Lubricated With N9 Safe To Use?
3. How Do Warnings Apply to N9 Products Used With Barrier Methods?
G. Is N9 Safe for Women at Low Risk for HIV/AIDS and STDs?
H. Is N9 Safe for Rectal Use?
I. Does N9 Increase the Risk of STDs Other Than HIV?
J. What Issues Did Other Comments Discuss?
1. Why Did FDA Define Frequent Use of N9 as "More Than Once a
Day"?
2. Should "Pharmacist" or "Health Care Provider" Be Included on
the Label?
3. What Does "Unprotected Sex" Mean?
4. What Does the Word "Irritation" Mean When Referring To
"Vaginal Irritation" in the Warning Language?
5. Should Warnings Be Printed in Both English and Spanish?
III. FDA's Final Conclusions on Warnings and Other Labeling Information
for OTC Vaginal Contraceptive and Spermicide Drug Products Containing
N9
A. New Labeling Requirements
B. Statement About Warnings
IV. Analysis of Impacts
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Federalism
VIII. References

I. Background

In the Federal Register of January 16, 2003 (68 FR 2254), FDA (we)
published a proposed rule (the proposed rule) to require new labeling
warning statements for all OTC vaginal contraceptive drug products
containing N9. These proposed warning statements are intended to advise consumers that vaginal contraceptives containing N9 do not protect against infection from HIV, the virus that causes AIDS, nor against getting other STDs. The warnings also would advise consumers
that frequent use of vaginal contraceptives containing N9 can increase
vaginal irritation, and that increased vaginal irritation from the use
of N9 may increase the possibility of becoming infected with the AIDS
virus (HIV) or other STDs from infected partners. The proposed rule
contains the data and scientific evidence that we considered to require
these warnings.

N9 is a nonionic surfactant that works as a vaginal contraceptive
(spermicide) by damaging the cell membrane of sperm. As stated in the
proposed rule (68 FR 2254 at 2255), there are in vitro studies showing
that N9 causes damage to the cell wall of certain STD pathogens and has
activity against certain bacterial and viral STD pathogens, including
HIV. Because N9 inhibits the replication of the AIDS virus (HIV) and
other STD pathogens in vitro, it has been suggested over the years that
N9 might help prevent or reduce the risk of transmission of the AIDS
virus and other STDs in humans (68 FR 2254 at 2255). Thus, research was
undertaken to see if N9 would prevent HIV and STDs. In the proposed
rule, FDA discussed the evidence that demonstrates that N9 does not
prevent or reduce the risk of transmission of the AIDS virus and other
STDs in humans (68 FR 2254 to 2259). FDA also discussed recent
scientific data that suggest that frequent use of N9 may increase the
risk of HIV infection for women at risk for HIV (68 FR 2254 to 2259).
Thus, FDA issued the proposed rule to provide a clear, consistent
message that N9 is not effective in preventing HIV transmission, and
that N9 can facilitate transmission of the disease. We also proposed
labeling (warnings and other information) to encourage the use of
condoms as a method to help sexually active persons reduce the risk of
becoming infected with the AIDS virus (HIV) and other STDs. We
requested feedback on whether the proposed warnings adequately convey
the safety concerns about N9 and whether there are additional data to
support, expand, or refute the proposed warnings.

In response to the proposed rule, we received 153 comments. Two
comments were submitted from industry, 8 from consumer advocacy groups,
10 from health associations, 16 from health professionals, and 117 from
individual consumers. These comments are on display in the Division of
Dockets Management. For access to the docket to read background
documents or comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number (s), found in brackets in the
heading of this document, into the "Search" box and follow the
prompts and/or go to the Division of Dockets Management, 5360 Fishers
Lane, rm. 1061, Rockville, MD 20852. We are responding to the comments,
and discussing some additional data that has come to our attention, in
this document.

The majority of comments from consumers, consumer advocacy groups,
health organizations, and health professionals supported FDA for
proposing warnings for N9 vaginal contraceptive OTC drug products that
inform consumers that N9 does not protect against HIV and other STDs
and that frequent use (more than once a day) may increase the risk of
infection of HIV from infected partners. The comments stated that the
proposed warnings will inform consumers of the risks so that they can
make responsible health care decisions. Forty-six consumers reported
getting vaginal irritation, burning, itching, swelling, or increased
yeast and urinary infections after using contraceptive products
containing N9. These comments stated that the proposed labeling is
necessary to warn consumers of the risks related to irritation
associated with N9 and to educate consumers who mistakenly believe that
vaginal contraceptives/spermicides containing N9 also prevent STDs.

Some comments did not support the proposed warnings. Other comments
asked for clarification of the warning language, recommended changes in
the wording of the warning language, or provided data to expand the
proposed warnings. After reviewing the comments, FDA has revised the
proposed warnings in this final rule. The differences between the
warning language in the proposed and final rules are as follows:

Table 1.--Differences in the Warning Language in the Proposed and Final Rules

Proposed Rule

Final Rule

"For vaginal use only"

"For vaginal use only
Not for rectal (anal) use"
We explain the reason for this change in section II.H, comment 12, of this document.

"Sexually transmitted diseases (STDs) alert: This product does not protect against the AIDS virus (HIV) or other STDs"

"Sexually transmitted diseases (STDs) alert:
This product does not protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner"
We discuss this change in section II.B.2, comment 3 of this document.

"Ask a doctor before use if you
have

a new sex partner, multiple sex partners, or unprotected sex. Frequent use (more than once a day) of this product can increase vaginal irritation, which may increase the risk of getting the AIDS virus(HIV) or other STDs from infected partners. Ask a doctor or other health professional for your best birth control method."

"Do not use if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control.""When using this product you may get vaginal irritation (burning,
itching, or a rash)
"We discuss these changes in sections II.B.2, comment and
3 II.C, comment 5 of this document.

"Studies have raised safety concerns that frequent use (more than once a day) of products containing nonoxynol 9 can increase vaginal irritation, which may increase the risk of getting the AIDS virus (HIV) or other STDs from infected partners. Vaginal irritation may include symptoms such as burning, itching, or a rash, or you may not notice any symptoms at all. If you use these products frequently and/or have a new sex partner, multiple sex partners or unprotected sex, see a doctor or other health professional for your best birth control and methods to prevent STDs."

"studies have raised safety concerns that products containing the spermicide nonoxynol 9 can irritate the vagina and rectum. Sometimes this irritation has no symptoms. This irritation may increase the risk of getting HIV/AIDS from an infected partner"
We discuss this change in section II.B.2, comment 3 of this document.

"you can use nonoxynol 9 for birth control with or without a diaphragm or condom if you have sex with only one partner who is not infected with HIV and who has no other sexual partners or HIV risk factors".
We discuss this change in sections II.F.3, comment 10 and II.G, comment 11 of this document.

"use a latex condom without nonoxynol 9 if you or your sex partner has HIV/AIDS, multiple sex partners, or other HIV risk factors".
We discuss this change in section II.F.2, comment 9 of this document.

"ask a health professional if you have questions about your best birth control and STD prevention methods".
We discuss this change in section II.J.2, comment 15 of this document.

"correct use of a latex condom with every sexual act will help reduce the risk of getting the AIDS virus (HIV) and other STDs from infected partners".

"when used correctly every time you have sex, latex condoms greatly reduce, but do not eliminate, the risk of catching or spreading HIV, the virus that causes AIDS.
We discuss this change in section II.F.1, comment 8 of this document.

Use of N9 products may increase the risk of HIV and other STDs.

Use of N9 products is associated with an increased risk of HIV.
We discuss this change in sectio II.I, comment 13 of this document.

We describe and respond to the comments received in section II of
this document.

II. Comments on the Proposed Rule and FDA's Responses

A. Should N9 Remain Available as an Active Ingredient in OTC Vaginal
Contraceptive Drug Products?

(Comment 1) Some comments stated that N9 vaginal contraceptive drug
products should be removed from the OTC market or changed from OTC to
prescription status for the following reasons:

N9 does not protect against HIV or STDs.

N9 causes damage to the vaginal lining and increases the
risk of contracting HIV due to this vaginal irritation.

Many new cases of HIV and STDs will develop if
contraceptives with N9 are available without consultation with a health
professional.

Consumers who may not see, read, understand, or follow the
advice contained on the warning labels need to be protected from the
risks of using N9. They should have to see a health professional before
using products containing N9.

Some of these comments also suggested that, alternatively,
manufacturers should be required to reformulate their products with
other safe and effective spermicides or microbicides.

Many other comments stated that N9 products should remain an OTC
contraceptive option for women at low risk for HIV infection for the
following reasons:

N9 products are effective in preventing pregnancy,
particularly when used with a barrier method such as a condom or
diaphragm.

N9 products are a contraceptive option for women who
cannot tolerate hormone-based birth control methods.

N9 products are a contraceptive option for women at low
risk for HIV and STDs.

N9 products represent one of the few methods available for
women that are controlled by women.

N9 products offer a "substantial" benefit to a "small
but important" group of users.

(Response) FDA does not agree that vaginal contraceptive drug
products containing N9 should be removed from the OTC marketplace. As
part of FDA's review of the safety and effectiveness of this class of
OTC drugs, the Advisory Review Panel on OTC Contraceptives and Other
Vaginal Drug Products classified N9 as Category I (safe and effective)
as a spermicide for the prevention of pregnancy on December 12, 1980
(45 FR 82014 at 82028). Comments were received following publication of
the panel's report and additional scientific data became available. FDA
published the proposed rule on OTC vaginal contraceptive drug products
on February 2, 1995 (60 FR 6892). In that proposed rule, FDA considered
N9 safe as a vaginal contraceptive; however, data indicated that its
effectiveness in final product formulations was highly variable.
Therefore, FDA proposed clinical trials for N9 spermicidal products to
validate their effectiveness in final formulations.

In November 1996, four FDA advisory committees (Nonprescription
Drugs, Reproductive Health Drugs, Antiviral Drugs, and Anti-infective
Drugs) met to discuss the type and quality of data needed to support
and ensure the spermicidal effectiveness of N9 in final formulations.
The advisory committees concluded that the existing data provided
evidence of some effectiveness, but they had concerns about variability
in dose, different formulations, and duration of effect. The advisory
committees recommended that FDA allow interim marketing of N9 vaginal
contraceptive drug products pending further clinical trials (68 FR 2254
at 2255).

Current data suggest that the number of women out of 100 who become
pregnant in the first year of typical use of N9 spermicide drug
products is as follows (Ref. 1):

16 for the diaphragm with spermicide.

16 to 32 (depending on whether the women have had prior
births) for the cervical cap with spermicide.

29 for spermicides alone (gel, cream, foam, film,
suppository).

The number of women who become pregnant using no contraception is 85
out of 100 (Ref. 1). The Centers for Disease Control and Prevention
(CDC) (Ref. 2) report that the combined use of diaphragms with N9
spermicide prevents approximately 460,000 pregnancies in the United
States each year. It is important to the public health that consumers
have access to multiple methods of contraception to choose from that
help prevent unplanned pregnancy.

FDA is currently reviewing newly published data regarding the
efficacy of N9 containing spermicides (Ref. 3), and we will publish our
conclusions in a future issue of the Federal Register. These data are
from a clinical trial which compares the effectiveness and safety of
five spermicides, which include three gels containing 52.5 milligrams
(mg), 100 mg, and 150 mg of N9 per dose and a film and a suppository,
each containing 100 mg of N9 per dose. In the meantime, based on its
history of safety and effectiveness, we have determined that N9 should
remain on the market while we complete our review. Based on the
information currently available, we have also determined that women at
low risk for HIV can safely use N9 products for their contraceptive
needs and that the intervention of a doctor or health care provider is
not necessary.

B. What Issues Were Raised by Comments That Did Not Support the
Proposed Warning Statements?

1. Will Warning Labels Be Seen, Understood, or Followed?

(Comment 2) Two comments stated that FDA's proposed warnings may
not adequately protect consumers against the health risks posed by N9
products because consumers may not see, read, understand, or follow the
advice contained on the warning labels. One of the comments referred to
a study sponsored by the National Council on Patient Information and
Education (NCPIE), conducted in 2001, which surveyed adult consumers
and health care professionals on the self-medicating behaviors of the
American public. The comment stated that the survey clearly established
that consumers do not consistently read caution labels. The comment
also mentioned a 1997 study by "Sansgiry et al." of industry labeling
practices which stated, according to the comment, that as the OTC
package size increased, the font size used for the product increased,
except that the font size for warnings remained constant. The comment
stated that the study also showed that 22 percent of the product
packages examined used smaller than 6-point font type for warnings. The
comment concluded from this study that consumers may have difficulty
seeing and reading the N9 warning language. The second comment stated
that many consumers consider OTC drug products to be safe and present
no risks because they are available without a prescription. Thus,
consumers may ignore the product labeling because of this false
impression. The comment recommended that FDA use consumer surveys and
focus groups to test for comprehension of the proposed labeling before
publishing a final rule mandating specific language.

(Response) FDA thinks that the warning statements for N9 vaginal
contraceptive drug products will be seen, read, understood, and
followed by consumers. We are aware of the studies cited by the
comment, i.e., the Sansgiry, Cady, and Patil study (Ref. 4), which
described OTC industry labeling practices at that time, and the NCPIE
study (Ref. 5) that examined the self-medicating behaviors of the
American public, including what information consumers seek when reading
an OTC drug product label. These studies reinforced the need for FDA to
improve the OTC drug product label and also to enhance educational
programs to teach consumers about the risks and benefits of OTC drugs.
FDA issued new labeling requirements for OTC drug products on March 17,
1999 (64 FR 13254). This labeling regulation, codified in 21 CFR
201.66, requires OTC drug products to be labeled with a standardized
"Drug Facts" label. The "Drug Facts" label offers a more
structured, organized, and compact presentation of the product
information, which allows consumers to process the information with
improved understanding, and provides clear signals regarding important
information. The new requirements include a 6-point minimum type size,
and bolded type headings and subheadings. When the warning requirements
in this final rule for OTC vaginal contraceptive drug products
containing N9 become effective, all manufacturers will be required to
revise their label using the "Drug Facts" format. Use of the revised
labeling in the "Drug Facts" format will enable consumers to better
read and understand the information presented and apply the information
to the safe and effective use of OTC vaginal contraceptive drug
products.

Additionally, FDA is involved in various initiatives to encourage
awareness of the safe and effective use of drugs and the importance of
reading drug labels. FDA provides consumer articles, public service
announcements, websites, etc., and also partners with many
organizations to promote better understanding of the risks and benefits
of drug products. For example, in cooperation with FDA, the Consumer
Healthcare Products Association (CHPA) and NCPIE's "Be MedWise"
campaign provide information to consumers on the new OTC drug labels.

2. "Are the Warnings Supported by the Scientific Literature?"

(Comment 3) Three comments stated that FDA's proposed warning
language for N9 vaginal contraceptive drug products implies a link
between the use of N9 and an increased risk of HIV that is not
sufficiently supported by the scientific literature. These comments
stated that the proposed warnings will frighten consumers in a manner
that could affect the continued availability of a safe and effective
contraceptive. The first comment contended that FDA relies primarily on
two studies to support its position that there is a link between the
use of N9 vaginal contraceptive drug products and an increased risk of
HIV infection as follows: (1) The Van Damme et al. study (2002) (Ref.
6) and (2) the Kreiss et al. study (1992) (Ref. 7). The comment
provided the following reasons why the Van Damme et al. study should
not be used to support FDA's proposed warnings for N9 products:

Twenty percent of the study subjects were lost to followup
(so the investigators never determined the HIV status of these
participants).

The results between the two test groups (N9 and placebo)
were "barely" significant (p=0.047).

The placebo may have had a protective effect.

A much higher number of unprotected anal sex acts were
reported from one of the study centers (Durban) where the most HIV
seroconversions (conversions from HIV negative status to HIV positive
status) occurred.

The comment also contended that the Kreiss et al. study should not be
used to support FDA's proposed warnings for N9 products because:

The study was terminated early when it was determined that
the HIV seroconversion results became inconsistent with the hypothesis
that N9 has a clinically beneficial effect in preventing HIV. The statistical analysis of the data at the time the study was terminated did not support a statistically significant
conclusion that N9 increased the risk of HIV transmission.

The sponge dosage form could raise safety issues not
associated with other dosage forms.

This comment added that FDA did not consider the results and
conclusions of two other studies, Roddy et al. (1998) (Ref. 8) and
Richardson et al. (2001) (Ref. 9). The comment stated that these
studies either support a conclusion opposite to the Van Damme et al.
and Kreiss et al. studies or weaken the conclusion that frequent use of
N9 vaginal contraceptives increases the risk of HIV infection from an
infected partner. The comment concluded that the link between N9 use
and an increased risk of HIV infection is speculation. The comment
requested that FDA remove the following proposed warning language that
links N9 use with an increased risk of HIV infection:

"Ask a doctor before use if you have a new sex partner,
multiple sex partners, or unprotected sex. Frequent use (more than once
a day) of this product can increase vaginal irritation, which may
increase the risk of getting the AIDS virus (HIV) or other STDs from
infected partners. Ask a doctor or other health professional for your
best birth control method."

"Studies have raised safety concerns that frequent use
(more than once a day) of products containing nonoxynol 9 can increase
vaginal irritation, which may increase the risk of getting the AIDS
virus (HIV) or other STDs from infected partners. Vaginal irritation
may include symptoms such as burning, itching, or a rash, or you may
not notice any symptoms at all. If you use these products frequently
and/or have a new sex partner, multiple sex partners, or unprotected
sex, see a doctor or other health professional for your best birth
control and methods to prevent STDs."

The comment recommended the following language, which it contended more
accurately reflects the known science and places the warnings in a more
relevant context:

"Ask a doctor before use if you have frequent sex (more
than three times a day). Frequent use (more than three times a day) of
nonoxynol 9 may increase vaginal irritation, which may increase the
risk of getting the AIDS virus (HIV) or other STDs from infected
partners. Ask a doctor or other health professional for your best birth
control method."

"Studies concerning some nonoxynol 9 formulations (i.e.,
gel and sponge) in high risk populations (i.e., prostitutes) have
raised very preliminary safety concerns that frequent use (more than
three times a day) of products containing nonoxynol 9 can increase
vaginal irritation, which may increase the risk of getting the AIDS
virus (HIV) or other STDs from infected partners. Other studies have
shown no such risk for certain formulations (i.e., nonoxynol 9-
containing film and gel) in these high risk populations. Vaginal
irritation may include symptoms such as burning, itching, or a rash, or
you may not notice any symptoms at all. While there is no clear link
between the frequent use of nonoxynol 9 and the increased risk of HIV
infection or other STDs from infected partners, if you use these
products frequently, see a doctor or other health professional for your
best birth control and methods to prevent STDs."

The second comment stated that the Van Damme et al. study results
are "exploratory" and that the study's "generalizability" is a
problem because the subjects were sex workers and had highly
"atypical" sexual activity. This comment contended that previous
trials of N9, conducted in sex workers, have shown conflicting results
and, taken together, do not show a harmful or a protective effect. The
third comment expressed similar concerns about the Van Damme study's
generalizability.

(Response) FDA believes that the proposed warning language, which
implies a link between frequent use of N9 vaginal contraceptive drug
products and an increased risk of HIV, is supported by the scientific
literature. As discussed elsewhere in this document, we are deleting
the term "frequent" from the labeling requirements of this final rule
because we believe that if a woman is at risk of HIV/AIDS, she should
not be using N9 products, regardless of the frequency of use (see
section J.1 of this document). In the proposed rule, FDA cited many
studies that demonstrated that daily use of N9 products causes vaginal
irritation (i.e., inflammatory changes in the epithelial cells lining
the vagina and disruption of these epithelial cells), and causes
disruption of the vaginal flora (68 FR 2254 at 2254 to 2258). Some
studies suggested that the risk of these adverse events can be
increased by frequent or chronic use of N9 products. In general, the
various studies cited in the proposed rule defined infrequent or low
frequency use as "use once a day or less." It appears from these
studies that infrequent use does not result in an increased rate of
epithelial disruption. Therefore, FDA defined frequent use in the
proposed rule as "more than once a day" and believes that the
scientific literature supports the statement that frequent use (more
than once a day) can increase vaginal irritation.

In the proposed rule, FDA discussed studies that demonstrated that
frequent use of N9 products causes increased disruption of the vaginal
epithelium which may increase the risk of transmission of the AIDS
virus (HIV). The most pivotal of these studies is the Van Damme et al.
study (cited at 68 FR 2254 at 2255) (Ref. 6). This was a randomized,
placebo-controlled clinical trial to assess the effectiveness of a
vaginal gel containing N9 on HIV-1 transmission in female sex workers
in Africa and Thailand, all at high risk for HIV. The study gel (COL-
1492) contained 52.5 mg N9 (other constituents included a bioadhesive
carbomer). The placebo gel differed from COL-1492 in that it did not
contain N9 and had more carbomer. At enrollment, women received a
supply of study gel (N9 or placebo) and male condoms to use until the
next visit. Women were asked to return to the clinic every month for a
follow-up visit. There was no limit on the number of gel doses that
could be used per day. The primary endpoint of the study was incident
HIV-1 infection. Secondary objectives included the effectiveness of
this drug in prevention of chlamydial infection, gonorrhea,
trichomoniasis, and genital ulcer disease, and safety and acceptability
of the gel under situations of long-term use. The treatment period was
48 weeks.

A total of 765 women were included in the primary analysis (376 in
the N9 group and 389 in the placebo group) and 563 women completed the
48-week study. The overall retention rate of the participants in the
study was 71 percent after 24 weeks and 68 percent after 48 weeks,
which is similar to rates projected by the study investigators for
their sample size (60 percent retention per year).

Of the 765 women, 59 in the N9 group and 45 in the placebo group
seroconverted from HIV-1 negative to HIV-1 positive. Women who used an
N9 vaginal gel had a significantly higher risk of becoming infected
with HIV-1, compared with women using the placebo gel (p=0.047). The
HIV-1 incidence per 100 women-years was 14.7 for the N9 group and 10.3 for the placebo group. This conclusion
did not change when statistical adjustments were made for differences
in the frequency of vaginal and anal sex not protected by condoms.

To test the hypothesis of dose-dependent toxic effects of N9, the
investigators divided the mean gel use per working day into three
categories based on tertiles. The investigators compared HIV-1
incidence per treatment group and per category of gel use. HIV-1
incidence increased with increasing gel use in the N9 group versus the
placebo group. In the N9 group, HIV-1 incidence rose from 8.8 per 100
woman-years in women reporting mean use of 3.5 or fewer applicators per
day to 30.6 in women reporting a higher mean daily use (hazard ratio
3.5; 95% Confidence Interval (CI) 2.1-5.8; p< 0.0001). In the placebo
group, HIV-1 incidence in those categories was 8.1 and 14.5 per 100
woman-years, respectively (1.8; CI 1.0-3.3, p=0.05). It is important to
note that this analysis simply suggests a dose response between the
amount of gel used per day and the risk of HIV-1 infection. The data
does not support a conclusion that using less than 3.5 applications of
N9 per day is associated with an incidence risk for HIV-1 infection
similar to placebo. Dividing the data by other methods (e.g., into
quartiles), would identify other amounts of N9 per day supporting an
association between the amount used and increasing risk.

The study also investigated the frequency of N9 use and the
incidence of lesions with epithelial breach, and whether the risk of
HIV transmission increases with increasing number of lesions with
epithelial breach. They found that the incidence of lesions with an
epithelial breach rose with increasing gel use. The increase in
incidence of lesions with an epithelial breach was seen in both the
placebo and N9 groups, but it happened most rapidly in the N9 group.

FDA finds that one comment's concern about certain aspects of the
Van Damme et al. study are valid as follows:

There was a high loss to followup rate overall (retention
rate was 68 percent at 48 weeks). However, the study was designed with
an assumption of an annual retention rate of 60 percent.

There was a higher loss to followup rate in the N9 group
compared to the placebo group.

The highest rates of both seroconversion and retention
were observed at the largest center in the study (Durban). This center
also reported the highest rate of anal sex.

Although the study was not flawless, it was a large, well designed,
randomized, placebo-controlled, multi-center clinical trial. Both the
treatment and placebo groups were balanced with respect to baseline
characteristics. Even with the noted limitations, we believe that the
study is evidence that N9 may increase the risk of HIV-1 infection in a
population already at increased risk for HIV-1 infection.

The comment also expressed concerns about the Kreiss et al. study
(Ref. 7) that we cited in the proposed rule (68 FR 2254 at 2257). In
this study, HIV negative sex workers in Nairobi, Kenya used either a
vaginal sponge containing 1,000 mg N9 or a placebo. Women using the N9
sponge had a higher conversion from HIV negative to HIV positive. A
total of 21 women (43 percent) of the N9 group and 19 women (35
percent) of the placebo group converted from HIV negative to HIV
positive. We acknowledge the study's shortcomings, as noted in the
comment. However, we believe that early termination of the study for
safety reasons (i.e., that the seroconversion results had become
inconsistent with the hypothesis of clinically beneficial effects of N9
in preventing HIV seroconversion) was ethically appropriate, and
suggests an outcome consistent with the results of the Van Damme et al.
study.

The comment contends that two other studies, Roddy et al. (Ref. 8)
and Richardson et al. (Ref. 9), support a conclusion opposite to the
Van Damme et al. and Kreiss et al. studies or weaken the conclusion
that use of N9 spermicide products may increase the risk of HIV
infection from an infected partner. We do not agree. The Roddy et al.
study was conducted to determine whether a 70-mg N9 vaginal film
provided protection against HIV, gonorrhea, or chlamydia. The study
population consisted of 1,170 HIV-negative female sex workers (575 in
the placebo group, 595 in the N9 group) residing in Cameroon, Africa,
who averaged at least 4 sexual partners per month. The study results
showed no difference in the rate of HIV transmission in the N9 group
versus the placebo group (48 vs. 46, respectively), although the
incidence of genital lesions was slightly higher in the N9 group. The
results from this study, while not consistent with the data from the
Van Damme et al. study, do not invalidate the Van Damme et al. study
results. Roddy et al. reported the total number of sexual acts for
placebo and N9 users but did not report the average number of sexual
acts per day or per week. There were 595 study participants in the N9
group who recorded a total of 147,996 coital acts. The average length
of study followup was 14 months. This averages out to 1 coital act
every 1.7 days. The study participants may not have used the N9 film
often enough to demonstrate a difference in HIV risk compared to those
using the placebo product. The results of the Roddy et al. study do not
diminish the importance of the safety signal observed in the Van Damme
et al. study. We believe that concerns about an increased risk of HIV
transmission with frequent N9 use would apply to all products
containing N9, regardless of the formulation. We do not agree with the
comment's suggestion that the proposed warnings be revised to read
"Other studies have shown no such risk for certain formulations (i.e.,
N9 film and gel) in these high risk populations".

The Richardson et al. study was conducted to determine the effect
of a 52.5 mg N9 gel on the acquisition of STDs in HIV negative sex
workers in Kenya. The study enrolled a relatively small number of
subjects (total of 278 women, 139 in the N9 group and 139 in the
placebo group) at only one clinic site. The sample size and the low
extent of exposure may not have been sufficient to detect rare events.
The authors stated that women enrolled in the Richardson et al. study
came from another ongoing prospective cohort study at the same clinic
site. Selection of subjects from that study population might have
introduced confounding factors into their study. There was relatively
low frequency of sexual intercourse and exposure to the test products
(median of twice a week). The median compliance with product use was 75
percent in the N9 group and 80 percent in the placebo group (median
compliance was 78 percent; the range was 0 to 100 percent). However,
only 32 percent of the women in the N9 group and 36 percent of the
women in the placebo group were 100 percent compliant. It is not clear
how reliable the data collection methods were. The study did not
mention if women kept a diary of product use and frequency of sexual
intercourse, or if this information was collected by the study staff
during the follow-up visits. For all of these reasons, we conclude that
this study cannot be reliably used to support the comment's
contentions.

In conclusion, FDA does not accept the first comment's request to
remove the proposed warning language that links N9 use with an
increased risk of HIV infection. FDA is providing information about
whether it is safe for consumers to use these products based on their risk for HIV and STDs. Based on the available scientific
evidence, we have determined that women should be advised that use of
N9 can cause vaginal irritation and that use of N9 has been associated
with an increased risk for HIV transmission in women at high risk for
HIV/AIDS. Use of N9 can result in irritated and inflamed genital tissue
and may increase a person's risk of getting HIV/AIDS if they have sex
with an HIV infected partner. We are, however, revising the proposed
warnings to more clearly convey the message that N9 spermicides cause
vaginal irritation, may increase the risk of getting HIV from an
infected partner, and should not be used by women at high risk for HIV/
AIDS. The warnings in Sec. 201.325(b)(2) and (b)(3) of the proposed
rule stated:

Sexually transmitted diseases (STDs) alert:
This product does not protect against HIV/AIDS or other STDs

Ask a doctor before use if you have

a new sex partner, multiple sex partners, or unprotected
sex. Frequent use (more than once a day) of this product can increase
vaginal irritation, which may increase the risk of becoming infected
with the AIDS virus (HIV) or other STDs from infected partners. Ask a
doctor or other health professional for your best birth control method.

The revised warnings in this final rule appear under the subheadings
"Sexually transmitted diseases (STDs) alert," "Do not use," and
"When using this product" and state:

Sexually transmitted diseases (STDs) alert: This product does not
protect against HIV/AIDS or other STDs and may increase the risk of
getting HIV from an infected partner.

Do not use if you or your sex partner has HIV/AIDS. If you do not
know if you or your sex partner is infected, choose another form of
birth control.

When using this product you may get vaginal irritation (burning,
itching, or a rash).

We are also revising the additional labeling information in
proposed Sec. 201.325(c)(1) (redesignated as Sec. 201.325(d)(1) in
this final rule) to more accurately reflect the scientific literature
and to convey the message that N9 spermicides should not be used by
women at risk for HIV. (Rectal use of N9 is discussed later in section
II.H, comment 12 of this document.) The revised additional labeling
information states:

"Studies have raised safety concerns that products
containing the spermicide nonoxynol 9 can irritate the vagina and
rectum. Sometimes this irritation has no symptoms. This irritation may
increase the risk of getting HIV/AIDS from an infected partner."

3. Is FDA Required To Prove Actual Causation to Justify the Warnings?

(Comment 4) One comment stated that the proposed labeling implies a
link between the use of N9 and an increased risk of HIV infection that
is not sufficiently supported by the scientific literature. The comment
contended that the link between N9 use and an increased risk of HIV
transmission is "mere speculation" that is not suggested by a
comprehensive review of the scientific literature. In response to FDA's
statement that we need not show actual causation to mandate the
proposed warning, the comment stated that it disputes a lesser standard
unless FDA can show it will prevent a public harm. The comment
suggested that there is not a public harm to prevent, so actual
causation must be shown. The comment further asserted that the proof to
require this warning must be sufficient to avoid a determination that
the warning language requirement is arbitrary and capricious under 5
U.S.C. 706, and suggested that FDA has not provided such proof.

(Response) FDA disagrees with the comment. Based on a review of the
available data, FDA believes the known scientific evidence supports its
proposed warnings (see section II.B.2, comment 3 of this document).
Furthermore, FDA does not need a causal relationship to be definitely
established to mandate new warnings. To protect the public health, FDA
has determined that the warnings are necessary to ensure that these OTC
drug products continue to be safe and effective for their labeled
indications under ordinary conditions of use as those terms are defined
in the Federal Food, Drug and Cosmetic Act (the act). The warnings
reflect FDA's conclusion that there is reasonable evidence of a causal
relation between a clinically significant hazard and the drug.

Courts have upheld FDA's authority to issue regulations requiring
label warnings and other affirmative disclosures (see, e.g. Cosmetic,
Toiletry and Fragrance Ass'n v. Schmidt, 409 F. Supp. 57 (D.D.C. 1976),
aff'd without opn., Vic. No. 75-1715 (D.C. Cir., August 19, 1977), even
in the absence of a proven cause-and-effect relationship between
product usage and harm (see Council for Responsible Nutrition v. Goyan,
Civ. No. 80-1124 (D.D.C. August 1, 1980) (see also section III.B of
this document). Mandating the warnings included in this final rule does
not violate the Administrative Procedure Act's prohibition against
arbitrary and capricious conduct, because FDA's action is reasonable
based on the sufficiency of the available data and the need to protect
the public health.

C. Should Women Ask a Doctor Before Using N9 Products?

(Comment 5) Some comments did not agree with FDA's proposed warning
language which advises women to ask a doctor before using N9 vaginal
contraceptive drug products if they have a new sex partner, multiple
sex partners, or unprotected sex. The comments questioned the need for
women to consult physicians about the role of N9 in their pregnancy or
STD prevention strategies. One comment doubted that the average
physician could provide enough special expertise or insight about the
role for N9 in a planned sexual encounter with a new partner to offset
the inconvenience, discomfort, or cost of involving a health
professional. Several comments stated that it was unclear what a woman
should do before she is able to consult a physician (e.g., avoid sex,
use alternative methods). Some comments contended that women should be
given enough information in the labeling to empower them to act
directly, without a health professional intermediary. These comments
recommended replacing "Ask a doctor before use" with explicit
statements such as "Women who may be at risk of HIV and who plan to
use the product more than once a day should consider another form of
birth control" or "If you use these products more often than once a
day and/or have a new sex partner, multiple sex partners, or
unprotected sex you should consider another form of birth control".
The comments suggested that adding a clarifying statement for women at
low risk and a statement that reinforces the use of latex condoms is
preferable to having consumers consult a physician for this
information.

(Response) FDA agrees with the comments that questioned the need
for women to have to consult with a physician before using N9 vaginal
contraceptive drug products if they have a new sex partner, multiple
sex partners, or unprotected sex. We try to provide consumers with the
appropriate information on the OTC drug product label to make informed
decisions on the use of these products. We believe that, by revising
the warning language under "Ask a doctor before use if you have" and
placing it under the subheadings "Do not use" and "When using this
product, "consumers will be able to make appropriate decisions
without consulting a physician. We consider this information
particularly important for women who do not see a physician regularly, who will not consult a
physician due to the expense, or who cannot get an appointment or
consultation with a physician in a timely manner. Therefore, as
discussed in section II.B.2, comment 3 of this document, we are
revising the warnings under "Ask a doctor before use if you have" and
placing them under the subheadings "Do not use" and "When using this
product."

We are also revising the additional labeling information proposed
in Sec. 201.325(c) to include more information about the use and
safety of N9, so women will not have to consult a physician before use.
We do not want to discourage consumers from speaking with physicians or
other health care providers at any time about important health issues
such as birth control and STD prevention. Therefore, we are including a
statement in the additional labeling information that women should ask
a doctor or other health professional for advice if they choose. The
revised additional labeling statements are discussed in sections
II.B.2, comment 3; II.F.1, comment 8; II.F.2, comment 9; II.F.3,
comment 10; II.G, comment 11; and II.J.2, comment 15 of this document.

D. Where Will the Warnings Appear in the Labeling?

(Comment 6) Several comments addressed the placement of the
proposed warning statements on the OTC package. The comments requested
that FDA require prominent placement of the proposed warning statements
on both the outer carton and package insert to warn consumers most
effectively. One comment recommended using large and bold font to help
attract the consumer's attention and encourage reading of the package
insert.

(Response) FDA is requiring that the warning statements discussed
in section II.B.2, comment 3 of this document (under the subheadings
"Do not use" and "When using this product"), the warning statements
discussed in section II.H., comment 12 of this document ("For vaginal
use only" and "Not for rectal (anal) use"), and the warning
statement under the subheading "Stop use and ask a doctor if" (under
Sec. 201.325(b)(4) in the proposed rule (68 FR 2254 at 2262)), appear
on the outside container or wrapper of the retail package, or on the
immediate container label if there is no outside container or wrapper,
in the Drug Facts labeling format, in accordance with Sec.
201.66(c)(7). We also proposed additional labeling information in Sec.
201.325(c) that could be placed either on the outside container or
wrapper of the retail package, under the "Other information" section
of the Drug Facts labeling, in accordance with Sec. 201.66(c)(7), or
in a package insert. In this final rule, the revised condom usage
statement, "when used correctly every time you have sex, latex condoms
greatly reduce but do not eliminate the risk of catching or spreading
HIV, the virus that causes AIDS." must be located in the Drug Facts
labeling under the heading "Other information" on the outside
container or wrapper of the retail package. The rest of the additional
labeling information now located in Sec. 201.325(d) of this final rule
can be located on the outside container or wrapper of the retail
package, under the "Other information" section of the Drug Facts
labeling in accordance with Sec. 201.66(c)(7), or in a package insert.
In instances where the manufacturer chooses to provide a package insert
for the additional information required in Sec. 201.325(d) of this
final rule, FDA recommends that a bolded statement such as "before
using this product read the enclosed package insert for complete
directions and information" be included on the outside container or
wrapper labeling to alert consumers and encourage reading of the
package insert.

E. Where Will the Condom Usage Statement Appear in the Labeling?

(Comment 7) Several comments requested that the proposed condom
message, "Correct use of a latex condom with every sexual act will
help reduce the risk of getting the AIDS virus (HIV) and other STDs
from infected partners," should directly follow the STD alert on the
outside container or wrapper as well as appear in a package insert so
that consumers are immediately advised that STD/HIV protection is
available OTC.

(Response) FDA agrees with the comments that information about HIV/
STD protection (i.e., condom use) is important information and is now
requiring that it be located on the outside container or wrapper in
close proximity to the STD alert and other pertinent warnings. Because
the information is not a warning, the statement appears in the Drug
Facts labeling, under the heading "Other information." In addition,
we are revising the condom usage statement (see section II.F, comment 8
in this document).

F. What Were the Comments on Condoms, Sexual Lubricants, and Barrier
Methods?

1. Do Warnings Apply to Condoms and Sexual Lubricants?

(Comment 8) Some comments questioned whether FDA's proposed
warnings apply to the labeling of condoms lubricated with N9. Several
comments noted that women using condoms and sexual lubricants
containing N9 may have a risk similar to those women using vaginal
contraceptives and so both groups need to receive the same warnings.
Some of these comments stated that FDA should propose warning language
similar to the proposed warnings for vaginal contraceptive products for
condoms and sexual lubricants containing N9, because of the substantial
public health risk posed by N9 containing products when used rectally.

(Response) This final rule requiring warnings for all OTC vaginal
contraceptives/spermicides containing N9 applies to drug products. It
does not apply to condoms lubricated with N9, which are primarily
regulated as medical devices (not drugs). Through rulemaking,
spermicidal condoms were classified as Class II medical devices (21 CFR
884.5310) and, as such, FDA's Center for Devices and Radiological
Health (CDRH) has primary jurisdiction over their regulation.

Although this final rule does not apply to condoms lubricated with
N9, it does contain information for consumers about using condoms as a
method to help reduce the risk of becoming infected with the AIDS virus
(HIV) and other STDs. In the January 16, 2003, proposed rule, FDA
discussed the public health benefit of such information and proposed
the following condom usage statement for spermicides containing N9:
"Correct use of a latex condom with every sexual act will help reduce
the risk of getting the AIDS virus (HIV) and other STDs from infected
partners" (see 68 FR 2254 at 2258 to 2259 and 2262). Subsequently, FDA
reviewed the labeling of condoms (with and without N9) and issued a
revised draft guidance (Ref. 10) on condom labeling. Therefore, FDA
revised the proposed condom usage statement to be consistent with the
statement it recommended in this new guidance. The new revised condom
usage statement (in Sec. 201.325(c) in this final rule) reads:
"[bullet] when used correctly every time you have sex, latex condoms
greatly reduce, but do not eliminate the risk of catching or spreading
HIV, the virus that causes AIDS."

Vaginal moisturizers and vaginal sexual lubricants are currently
being evaluated under the OTC drug review regulatory process. FDA
issued a call for data notice on December 31, 2003 (68 FR 75585),
requesting safety and effectiveness data on various products, including
vaginal moisturizers and vaginal lubricants. FDA will publish its
findings in a future issue of the Federal Register.

2. Are Condoms Lubricated With N9 Safe to Use?

(Comment 9) Some comments stated that labeling products containing
N9 with a warning that usage promotes the transmission of HIV or other
STDs may cause sexually active individuals to question whether or not
to use a condom at all. One comment expressed concern that after
reading FDA's proposed warnings, consumers would perceive that condoms
lubricated with N9 were not safe and would use nothing rather than use
a condom containing N9. Therefore, several comments stated that the
labeling should remind consumers that N9 is still effective in reducing
unwanted pregnancies and that we should continue to endorse the use of
spermicidal condoms. One of the comments stated that condoms containing
N9 provide important consumer and public health care benefits, because
N9 in condoms is intended to provide a secondary means of pregnancy
prevention if the condom is used incorrectly or breaks.

Other comments were not supportive of N9 condoms. One comment
requested that FDA take action to address the health risks posed by N9
as an additive to condoms and sexual lubricants by withdrawing them
from the marketplace. This comment stated that N9 is not necessary to
the function of lubricants and, in the case of condoms, N9 is not
necessary as an additive or lubricant to their function as a physical
barrier against pregnancy and disease. Several comments stated that the
correct and consistent use of condoms provides excellent protection
against pregnancy and HIV even without the addition of N9. One comment
concluded that since N9 lubricated condoms and sexual lubricants
containing N9 offer no proven benefit to any user group, and pose
substantial risks to some users, the risk should be eliminated rather
than relying on a "labeling" solution. One comment suggested revising
the proposed condom statement to read "Correct use of a (dry) latex
condom, (or a silicone lubricated latex condom, but NOT a condom
lubricated with N9) with every vaginal sexual act will help reduce the
risk of transmitting the AIDS virus (HIV) and other STDs."

(Response) As discussed in section II.F.1, comment 8 of this
document, this rulemaking does not apply to condoms that contain N9. It
does, however, provide for information to be added to labeling to
inform consumers about using condoms as a method to help reduce the
risk of becoming infected with the AIDS virus (HIV) and other STDs. In
section II.F.1, comment 8 of this document, FDA discussed a condom
usage statement to encourage the use of condoms as a method to help
reduce the risk of becoming infected with the AIDS virus (HIV) and
other STDs as proposed in the proposed rule. In the revised draft
guidance on condom labeling (Ref. 10) discussed previously, FDA
recommended the additional warning "if you or your partner has HIV/
AIDS, or you do not know if you or your partner is infected, you should
choose a latex condom without N-9". Because FDA wishes to provide
consistent information to consumers regarding products that contain N9,
we are including a new labeling statement in Sec. 201.325(d)(3) for
vaginal contraceptive drug products containing N9 to read as follows:
"[bullet] use a latex condom without nonoxynol 9 if you or your sex
partner has HIV/AIDS, multiple sex partners, or other HIV risk
factors."

3. How Do Warnings Apply to N9 Products Used With Barrier Methods?

(Comment 10) Some comments were concerned with how FDA's proposed
warnings apply to consumers using an N9 spermicide product with barrier
methods. The comments pointed out that FDA's proposed warning language
for vaginal contraceptive drug products containing N9 applies to
spermicide use alone, and not to concurrent use of N9 with female
barrier methods. The comments stated concerns about how consumers who
use N9 products with female barrier methods (such as diaphragms and
cervical caps) would apply FDA's proposed warning language to their
use. Several comments stated that consumers are currently advised
(e.g., in product labeling or by physicians) to use spermicide with
diaphragms and cervical caps to improve contraceptive effectiveness and
to insert more spermicide (without removal of the diaphragm or cervical
cap) if repeat intercourse occurs. The comments stated that FDA's
proposed labeling does not provide clear advice for women (particularly
those at low risk for HIV) who use these barrier methods. These
comments contend that there is not enough data about the effectiveness
of diaphragms or caps without additional spermicide to recommend
discontinuation of the spermicide. Some comments also stated that FDA's
proposed warning language may deter promotion and use of female barrier
methods that require additional spermicide. One of these comments
stated that a recent report from the CDC (Ref. 2) estimates that N9
used together with diaphragms prevents 460,000 pregnancies each year.
The comment stated that the proposed warning language would have a
harmful effect on women's health by increasing unintended pregnancies
and even STDs among women who would otherwise safely use cervical
barriers plus N9, but might switch to a less effective method or no
method at all. Another comment stated that clinicians may advise low-
risk clients not to use N9 as an adjunct to diaphragm use, which may
result in more unintended pregnancies. One comment suggested that FDA
advise consumers in the labeling that the studies that have found risks
associated with the use of N9 did not study the products with a
diaphragm or cervical cap.

(Response) Currently, FDA approved directions for use for cervical
caps (Ref. 11) and diaphragms (21 CFR 884.5350) specify use of a
spermicide with these devices. FDA believes that women using cervical
caps or diaphragms with N9 products are exposed to the same risks as
women who use N9 vaginal contraceptive drug products alone because of
the nature of the risk. The warning and other labeling information
statements that are required by this final rule will inform women how
best to use N9 spermicidal jellies and creams with barrier
contraceptive methods.

FDA agrees with the comments that women at low risk for HIV should
be able to safely use barrier methods along with N9 products and should
not be advised to change from a barrier contraceptive method. There
have been several studies over the years of cervical caps and
diaphragms using N9 that have shown minimal irritation to the vagina
and cervical mucosa (Refs. 12, 13, and 14). It is important to note
that these were contraceptive studies among women in stable, monogamous
relationships and that typical subjects did not use the devices
multiple times a day. In section II.G, comment 11 of this document, we
discuss labeling revisions that advise women at low risk for HIV that
N9 products continue to be safe for contraception for them.
Accordingly, FDA is also including barrier method and condom users at
low risk for HIV in these statements.

G. Is N9 Safe for Women at Low Risk for HIV/AIDS and STDs?

(Comment 11) A number of comments stated that women at low risk for
HIV and STDs should continue to use N9 spermicides as a contraceptive
option. One comment stated that some women who use N9 containing
vaginal contraceptive drug products for birth control may face a
different (lower) STD risk profile than the women studied in the
clinical trials, who were at a higher risk for HIV infection. The
comment stated that the proposed warnings might exert a harmful net
effect on women's health by increasing unintended pregnancy and STDs
among women who would otherwise use N9 products safely, but might
switch to less effective methods or no method at all because of the
warnings. The comment urged that the data need to be properly
extrapolated to women at lower risk for HIV who now use N9 products to
successfully prevent pregnancy. Another comment stated that until FDA
has additional data on the safety of N9 in low risk settings, women
currently using N9 containing spermicides for birth control should
continue to do so. Similarly, some comments stated that women at high
risk for HIV infection should not use N9 products for contraception,
but that these products should remain a contraceptive option for women
at low risk. These comments stated that if a woman is not at high risk
for HIV (because she is in a mutually monogamous relationship with a
HIV negative partner), then use of N9 products poses less of a safety
hazard. Thus, the comments contended that women at low risk for HIV
could safely use N9 products multiple times in a single day.

One comment stated that FDA should qualify the warning language
regarding "frequent use" for women who are at no or low risk for HIV.
The comment suggested that FDA add the following qualifying statements
to the labeling: "Women at low risk of HIV (i.e., those in a mutually
monogamous relationship with an HIV negative partner) can safely use
nonoxynol 9 (with or without a diaphragm) on multiple intercourse
occasions in a single day. Frequent use of nonoxynol 9 is only
problematic for women exposed to HIV and other STDs." A similar
comment stated that FDA must carefully word the warnings to provide
consumers with the ability to accurately assess the risks associated
with the product's use.

(Response) FDA agrees that many women who use N9 vaginal
contraceptive and spermicide drug products containing N9 have lower STD
and HIV risk profiles than the women studied in some of the clinical
trials discussed in the proposed rule (68 FR 2254) (e.g., the Van Damme
et al. study). We also agree that frequent use of N9 products poses no
risk of HIV transmission for an HIV negative woman who is in a mutually
monogamous relationship with an HIV negative partner. We believe that a
woman in such a relationship would not suffer any harm, other than
incurring vaginal irritation or epithelial lesions, from frequent use
of N9. Accordingly, we are revising the additional labeling information
proposed in Sec. 201.325(c)(1) (redesignated as Sec. 201.325(d)(2) in
this final rule) to include a new statement advising women that they
can continue to use N9 vaginal contraceptive and spermicide drug
products if they are at low risk for HIV. The statement reads:
"[bullet] you can use nonoxynol 9 for birth control with or without a
diaphragm or condom if you have sex with only one partner who is not
infected with HIV and who has no other sexual partners or HIV risk
factors."

H. Is N9 Safe for Rectal Use?

(Comment 12) Ten comments urged FDA to require a warning against
the rectal use of vaginal contraceptive drug products containing N9.
This is because N9 causes serious damage to the rectal epithelium that
may increase the risk of getting HIV or other STDs. The comments stated
that although the products are designed for vaginal contraceptive use,
they are routinely used for lubrication and (mistakenly) for protection
against STDs during anal intercourse. The comments stated that these
products are used rectally not only by the male homosexual population,
but also by heterosexual couples who engage in both vaginal and anal
intercourse. Two comments cited survey studies (Refs. 15 and 16)
showing that the routine use of these products within the homosexual
male population continues, due to the prevailing misperception that N9
protects against infection by sexually transmitted pathogens. Gross et
al. (Ref. 15) surveyed 3,093 gay men from 6 U.S. cities who reported
having anal intercourse during the previous 6 months. Of the 2,953 men
in the study who used lubricants during anal intercourse, 41 percent
actively sought N9 containing products. In another survey study
conducted in San Francisco and Oakland in 2001 by Mansergh et al. (Ref.
16), 41 percent (79) of 193 men who had anal sex with men during the
previous year used an N9 product without a condom. The men stated that
they believed that N9 provided some protection against HIV
transmission. The comment stressed that these data were collected after
the CDC and the San Francisco Department of Health issued warnings
about the dangers of using N9 rectally.

In further support of warnings against rectal use of N9, the
comments referred to several studies in animals (Refs. 17 and 18) and
one study in humans (Ref. 19) that showed that rectal application of N9
products causes damage to the cells lining the rectum. The comments
stated that this damage may compromise a barrier that protects against
viral and bacterial infection, thereby increasing the risk of HIV
transmission. One comment suggested the following warning: "Products
containing Nonoxynol-9 should never be used rectally; to do so may
substantially increase one's risk of contracting HIV from an infected
partner." Another comment requested that a warning against rectal use
be placed on the outer carton as well as in the package insert.

(Response) FDA agrees that products containing N9 should not be
used rectally. The studies provided by the comments show that the
rectal use of N9 damages the rectal epithelium in both animals and
humans (Refs. 17, 18, and 19). One study in mice (Ref. 17) showed that
pretreating the rectums of the mice with 2-percent N9 or with
spermicide products containing N9 before inoculation with herpes
simplex virus 2 (HSV-2) increased the likelihood of infection and
shortened the time until infection. In this study, the rectal
epithelium appeared to be repaired by 1 hour. The investigators stated
that although they chose to use HSV-2, the results could be generalized
to HIV transmission in humans because mouse and human epithelia are
morphologically similar and because the same type of target cells of
HIV, mononuclear blood cells, are present in the connective tissue and
become more numerous after tissue damage. A study in monkeys (Ref. 18)
investigated the effect of multiple applications of a 4-percent N9
product, placebo gel, or no product in three groups of monkeys. Each
group receiving test product or placebo gel got 1 daily intrarectal
application for 3 consecutive days, at 24 hour intervals. Before each
treatment, animals were given a saline (pretreatment) rectal lavage.
Test product was recovered by rectal lavage 15 minutes after
administration. Examination of rectal lavage samples indicated an
increase in the presence of epithelial cells and sheets of epithelium
15 minutes after N9 application, as compared with placebo gel and no-product groups. The investigators noted that 1 day after the first
exposure, epithelial sloughing was no longer evident, suggesting that
repair had occurred rapidly. However, the investigators noted the
continued presence of sloughed epidermal sheets 24 hours after repeated
product application, indicating a cumulative effect of N9 on rectal
tissues.

In a small study in humans, Phillips et al. (Ref. 19) investigated
the effects of rectal application of two OTC products containing 2-
percent and 1-percent N9, respectively, and two control formulations
(not containing N9) in four subjects (three men, one woman). The
experimental procedures were self-administered. After a baseline saline
rectal lavage, the four formulations were evaluated by placing each
test formulation in the rectum for 15 minutes via a syringe, at a
minimum of 72 hours between test formulations. After 15 minutes and
again 8 to 10 hours later, rectal lavage was performed. The
investigators showed that the rectal lavage collected 15 minutes after
N9 application revealed sheets of epithelium.

Sheets of rectal epithelium were not present in lavage fluid
collected 8 to 12 hours later, or after treatment with control
formulations. The authors concluded that N9 caused rapid exfoliation of
the rectal epithelium in humans, which is likely to make users more
susceptible to HIV infection.

Recently, Phillips et al. (Ref. 20) studied the effects of rectal
use of an OTC vaginal contraceptive drug product containing 2-percent
N9 in 18 human subjects. Thirteen of the study participants underwent
rectal evaluation at baseline and then at 15 minutes or at 2 hours
after N9 treatment. The remaining study participants underwent rectal
evaluation at 8 hours after treatment. A physician applied the test
formulation and did the rectal evaluation, which included biopsies as
well as lavage. The investigators observed sheets of epithelium in
lavage specimens collected at 15 minutes after N9 treatment. They
observed less material in specimens collected at 2 hours, but what they
collected appeared to be degraded cells and bacteria. In specimens
collected at 8 hours there was no evidence of cellular material.
Similarly, biopsies collected at 15 minutes appeared to be different
from baseline biopsies; the epithelial tissue appeared missing or
separated from the underlying submucosa. At 2 and 8 hours after
treatment, the epithelium appeared similar to the baseline specimens,
suggesting that the epithelium can repair itself within 2 hours. The
investigators concluded that N9 use should be avoided during anal sex,
because the rectal epithelium, which is rapidly exfoliated after a
single use of 2-percent N9, protects HIV target cells in the submucosa
from HIV infection.

We conclude that these data demonstrate that N9 is an irritant to
cells lining the rectum. The rectal epithelial damage that occurs with
N9 exposure could increase the risk of getting HIV from an infected
partner. Furthermore, a one-time rectal application of N9 is sufficient
to cause rapid sloughing of extensive areas of the rectal epithelium.
Accordingly, FDA is requiring a warning to inform users that these
products should not be used rectally. This warning is required to be
prominently displayed on the outside container or wrapper of the retail
package or the immediate container label if there is no outside
container or wrapper, in accordance with the requirements of Sec.
201.66(c). The warning states: "Not for rectal (anal) use" [in bold
type]. This warning follows the warning that reads "For vaginal use
only" [in bold type]. In addition, as discussed in section II.B.2,
comment 3 of this document, we are revising the additional labeling
proposed in Sec. 201.325(c)(1) to convey the message that studies show
that N9 can irritate the vagina and rectum and that this may increase
the risk of getting HIV/AIDS from an infected partner.

I. Does N9 Use Increase the Risk of STDs Other Than HIV?

(Comment 13) Two comments contended that there is no evidence that
N9 increases the risk of getting other STDs, such as Neisseria
gonorrhea (gonorrhea) and Chlamydia trachomatis (chlamydia). The
comments asked FDA to delete all referrals to a possible increased risk
of getting STDs other than HIV in its proposed warnings for vaginal
contraceptive drug products containing N9.

(Response) FDA agrees. While the Van Damme et al. study (Ref. 6)
suggested that frequent use of N9 increased the risk of HIV infection
compared with use of placebo in the population studied, it did not show
sufficient evidence of an increased risk of gonorrhea or chlamydia
infection. FDA is not aware of evidence suggesting a link between N9
use and increased risk of STDs other than HIV at this time.
Accordingly, we are revising the warnings for N9 vaginal contraceptive
and spermicide drug products to delete any reference to a possible
increased risk of getting STDs other than HIV when N9 is used by people
at risk for these infections. However, this does not affect the
warning, which we retain, that N9 does not protect against HIV or other
STDs.

J. What Issues Did Other Comments Discuss?

1. Why Did FDA Define Frequent Use of N9 as "More Than Once a Day"?

(Comment 14) Many comments addressed the definition of "frequent
use" in the proposed warning language for N9 containing vaginal
contraceptive drug products. FDA recommended that "frequent use" be
defined as "more than once a day." Several comments stated that this
definition is reasonable. One comment pointed out that many normal men
and women from "middle America," not just prostitutes, have sex
several times a day with their partners, and these consumers need to be
protected from the risks of using N9.

Other comments stated that FDA's rationale for proposing "frequent
use" as "more than once a day" is unclear. One comment contended
that in the Van Damme et al. study (Ref. 6), in which investigators
concluded that there was a statistically significant increase in the
risk of HIV infection from infected partners, N9 gel use was "more
than 3.5 times a day." The comment stated that when the product was
used less frequently than 3.5 times a day, there was no difference in
risk of HIV transmission between the N9 and placebo users.

Therefore, the comment stated that the definition of frequent use
should be changed to "no more than 3 times a day." One comment
contended that in the Van Damme et al. study, subjects averaged 3.6
coital acts a day, with a mean of 70 sexual acts a month, which is
atypical of the sexual activity for the majority of women worldwide.
Some comments questioned whether the results for commercial sex workers
in Africa and Thailand can be reasonably extrapolated to the general
U.S. population and questioned how the proposed definition of frequent
use, "more than once a day" was extrapolated from the study data.

Other comments claimed that frequent use, defined as "more than
once a day," overstates the risk for many women and seems very
restrictive. One comment proposed that women be informed that low
frequency use of N9 products has not been shown to increase HIV
infection rates, though it may increase vaginal irritation. Another
comment stated that if a woman is not at risk for HIV, then frequent
use of N9 poses no additional hazard. The comment proposed that women
at low risk for HIV could safely use N9 several times in a single day.

(Response) FDA proposed to define frequent use as "more than once
a day" because studies cited in the proposed rule (68 FR 2254 at 2257
to 2258) showed that if N9 is used more than once a day, the risk of
vaginal irritation and epithelial lesions increases. When this occurs,
the risk of HIV infection from infected partners increases according to
studies discussed in the proposed rule (68 FR 2254 at 2258). The one
comment erroneously concludes from the Van Damme et al. study that the
risk was only present if women used N9 more than 3.5 times per day. As
noted previously, the investigators analyzed dose response by dividing
N9 use into categories based on tertiles. The use category of greater
than 3.5 times per day identified the lower limit of the upper tertile.
The analysis does not identify a dose below which there is not an
increased risk. We are not aware of any available data to assist us in
identifying a dose of N9 where there is no increased risk for HIV-1
infection in a susceptible population. Because of the nature of the
risk, we believe that if a woman is at risk for HIV/AIDS, she should
not be using N9 products, regardless of the frequency of use.

In this final rule, we are eliminating references to "frequent
use" and revising the warning statements as described in section
II.B.2, comment 3 of this document. We also agree with the comments
that if a woman is not at risk for HIV, then frequent use of N9 poses
no additional hazard of HIV infection. Thus, women at low risk for HIV
can use N9 for birth control, with or without a diaphragm or condom,
regardless of frequency. Accordingly, we are revising the labeling
information to include a statement for women at low risk for HIV/AIDS
(see section II.G, comment 11 of this document). It is also important
to note that as explained in the response to section II.B.2, comment 3
of this document, the comment regarding risk only being present if
women used N9 more than 3.5 times a day is erroneous.

2. Should "Pharmacist" or "Health Care Provider" Be Included on the
Label?

(Comment 15) Some comments requested that the proposed warnings
that begin with the words "Ask a doctor" and "Stop use and ask a
doctor" be revised to include "health care provider," because
consumers receive health information from providers other than doctors.
Other comments suggested that FDA include the term "pharmacists" in
the labeling because pharmacists are the most accessible health
providers for consumers.

(Response) In this final rule, we revised the warnings proposed
after the subheading "Ask a doctor before use if you have" and moved
them to after the subheadings "Do not use" and "When using this
product." Therefore, whether the subheading states "Ask a doctor
before use" or "Ask a health care provider before use" is moot.
Regarding the use of the terms "doctor" and "health care provider"
in the subheadings "Ask a doctor before use if you have" and "Stop
use and ask a doctor if," FDA addressed this issue in the final rule
for labeling of OTC human drugs (64 FR 13254 at 13261 to 13262). FDA
acknowledged that in addition to physicians, other licensed
professionals play an important role in delivering clinical services
directly to consumers. FDA decided not to endeavor to list each
specific practitioner who is licensed and qualified and decided that
"doctor" is sufficiently broad and inclusive for this warning.
Nonetheless, we are including in the "Other information" statements
in Sec. 201.325(d) of this final rule, a statement that contains the
term "health professional" and advises women to ask a "health
professional" if they have questions about their birth control and STD
prevention methods. The statement reads: "[bullet] ask a health
professional if you have questions about your best birth control and
STD prevention methods".

3. What Does "Unprotected Sex" Mean?

(Comment 16) Several comments questioned use of the words
"unprotected sex" in the proposed warning language. The comments
asked FDA to clarify whether "unprotected sex" means sex without a
condom or sex without birth control.

The comments contended that the words "unprotected sex" are
confusing in the proposed "Other information" statement "if you use
these products frequently and/or have a new sex partner, multiple sex
partners, or unprotected sex, see a doctor or other health professional
for your best birth control and methods to prevent STDs" because sex
with N9 is not unprotected sex. One comment recommended using the words
"unprotected vaginal intercourse." Another comment recommended
replacing "unprotected sex" with the phrase "sex without condoms."

4. What Does the Word "Irritation" Mean When Referring To
"Vaginal Irritation" in the Warning Language?

(Comment 17) Two comments recommended that FDA not use the term
"irritation" when referring to "vaginal irritation" in the warning
language. The comments stated that epithelial disruption and
inflammation can occur in the absence of perceived symptoms of
irritation. Therefore, women who do not perceive what they believe is
"irritation" might mistakenly believe they are safe from N9 hazards.
The comments suggested that the proposed warning language ("Frequent
use (more than once a day) of this product may increase vaginal
irritation, which may increase the risk of getting the AIDS virus (HIV)
or other STDs from infected partners") be revised to read "Frequent
use of this product (more than once a day) can damage the cells lining
the vagina, a condition that may increase one's risk of becoming
infected with HIV or other STDs if exposed to an infected partner."

(Response) FDA understands the comments' concerns, but considers
the term "irritation" the proper term to use in the warning language.
This term is used throughout the scientific literature to describe the
effects of N9 on the vaginal epithelia. Because "irritation" is also
used widely in educational literature written for consumers, we believe
that this term has more meaning for consumers than "damage to the
cells lining the vagina." We recognize that vaginal irritation may be
asymptomatic; therefore, to protect women at risk for HIV, we advise
them in Sec. 201.325(b) in this final rule not to use N9 contraceptive
products at all. We are also including in the "Other information"
statements in Sec. 201.325(d) of this final rule a statement that
advises women that sometimes this irritation has no symptoms.

5. Should Warnings Be Printed in Both English and Spanish?

(Comment 18) One comment stated that it would be helpful to have
warnings in Spanish as well as English on the package label and the
package insert, with toll-free numbers and/or internet websites so that
consumers may obtain additional data or clarification.
(Response) FDA allows manufacturers to print their package label
and labeling in languages other than English. However, manufacturers
must adhere to certain requirements in 21 CFR 201.15(c)(1), (c)(2), and
(c)(3). Thus, FDA permits a dual label, e.g., a complete English label can be accompanied with a complete label in
Spanish, side by side. A package insert can be printed in English on
one side, and Spanish on the other. Also, manufacturers may include
toll-free numbers and internet websites in product labeling. If a
manufacturer wants to include this type of information within the Drug
Facts box, it must be done in accordance with Sec. 201.66(c)(9).

III. FDA's Final Conclusions on Warnings and Other Labeling Information
for OTC Vaginal Contraceptive and Spermicide Drug Products Containing
N9

A. Labeling Requirements

FDA is amending part 201 (21 CFR part 201) by adding Sec. 201.325
entitled "Over-the-counter drugs for vaginal contraceptive and
spermicide use containing nonoxynol 9 as the active ingredient;
required warnings and labeling information." This section will require
new warnings and other labeling information for all OTC vaginal
contraceptive and spermicide drug products containing N9 as the active
ingredient, whether marketed under a New Drug Application (NDA) or the
ongoing OTC drug review. The required warnings must be prominently
displayed on the outside container or wrapper of the retail package, or
the immediate container label if there is no outside container or
wrapper, in accordance with the requirements of Sec. 201.66(c), FDA's
labeling regulation (Drug Facts) for OTC drug products. FDA is
requiring that the following new warnings be added to the labeling of
all marketed OTC vaginal contraceptive/spermicide drug products
containing N9:

2. Under the heading "Warnings" the warning "Sexually
transmitted diseases (STDs) alert [in bold type]: This product does not
[this word in bold type] protect against HIV/AIDS or other STDs and may
increase the risk of getting HIV from an infected partner".

3. Under the subheading "Do not use," the warning "Do not use
[in bold type] if you or your sex partner has HIV/AIDS. If you do not
know if you or your sex partner is infected, choose another form of
birth control."

4. Under the subheading "When using this product," the warning
"When using this product [in bold type][optional, bullet] you may get
vaginal irritation (burning, itching, or a rash)".

5. Under the subheading "Stop use and ask a doctor if," the
warning "Stop use and ask a doctor if [in bold type][optional, bullet]
you or your partner get burning, itching, a rash, or other irritation
of the vagina or penis."

FDA is also requiring additional labeling information. This
information is to appear either on the outside container or wrapper of
the retail package, under the "Other information" section of the Drug
Facts labeling in accordance with Sec. 201.66(c)(7), or in a package
insert. The only exception is the statement in Sec. 201.325(c) about
the correct use of latex condoms, which must appear on the outside
container or wrapper of the retail package or the immediate container
label if there is no outside container or wrapper, under the "Other
information" section of the "Drug Facts" labeling. The additional
labeling information is as follows:

"studies have raised safety concerns that products
containing the spermicide nonoxynol 9 can irritate the vagina and
rectum. Sometimes this irritation has no symptoms. This irritation may
increase the risk of getting HIV/AIDS from an infected partner".

"you can use nonoxynol 9 for birth control with or
without a diaphragm or condom if you have sex with only one partner who
is not infected with HIV and who has no other sexual partners or HIV
risk factors".

"when used correctly every time you have sex, latex
condoms greatly reduce, but do not eliminate, the risk of catching or
spreading HIV, the virus that causes AIDS. [this information must
appear on the outside container or wrapper labeling in the Drug Facts
labeling under "Other information"].

"use a latex condom without nonoxynol 9 if you or your
sex partner has HIV/AIDS, multiple sex partners, or other HIV risk
factors".

"ask a health professional if you have questions about
your best birth control and STD prevention methods".

FDA is also recommending that all of the required warnings and
other labeling information be included in a package insert. Many
marketed OTC vaginal contraceptive and spermicide drug products already
have a package insert that contains information on how to use the
product, and this new information could readily be incorporated in the
package insert.

The following is an example of the Drug Facts labeling (for content
purposes only) for a vaginal contraceptive/spermicide drug product
containing N9 that incorporates all of the required new warnings and
labeling information on the Drug Facts label. The quantity of active
ingredient per dosage unit, the font sizes for title, headings,
subheadings, condensed text, and bullets, and other graphic features,
must be in accordance with Sec. 201.66.

BILLING CODE 6111-01-S

[GRAPHIC] [TIFF OMITTED] TR19DE07.033

BILLING CODE 6111-01-C

B. Statement About Warnings

Mandating warnings in an OTC drug product regulation does not
require a finding that any or all of the OTC drug products covered by
the regulation actually caused an adverse event, and FDA does not so
find. Nor does FDA's requirement of warnings repudiate the prior OTC
drug monographs and regulations under which the affected drug products
have been lawfully marketed. Rather, as a consumer protection agency,
FDA has determined that warnings are necessary to ensure that these OTC
drug products continue to be safe and effective for their labeled
indications under ordinary conditions of use as those terms are defined
in the act. This judgment balances the benefits of these drug products
against their potential risks. (See 21 CFR 330.10(a).)

FDA's decision to act in this instance need not meet the standard
of proof required to prevail in a private tort action (Glastetter v.
Novartis Pharmaceuticals Corp., 252 F.3d 986,991 (8th Cir. 2001)). To
mandate warnings, or take similar regulatory action, FDA need not show,
nor do we allege, actual causation. For an expanded discussion of case
law supporting FDA's authority to require such warnings, see the
December 6, 2002 (67 FR 72555), final rule entitled "Labeling of
Diphenhydramine-Containing Drug Products for Over-the-Counter Human
Use."

IV. Analysis of Impacts

In accordance with Executive Order 12866, FDA has previously
analyzed the potential economic effects of this final rule. As
announced in the proposal, the agency has determined that the rule is
not a significant regulatory action as defined by the Order. The agency
has not received any new information or comments that would alter its
previous determination.

FDA has examined the impacts of this final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes this
final rule is not a significant regulatory action under Executive
order.

The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the one-time costs to comply with this rule
are small, the agency certifies that the final rule will not have a
significant economic impact on a substantial number of small entities.

Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing "any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year." The current threshold after adjustment
for inflation is $127 million, using the most current (2006) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.

The purpose of this final rule is to require additional labeling
for OTC vaginal contraceptive and spermicide drug products containing
N9. The labeling includes new warnings and other important information
about using these products. These products are currently packaged in an
outer carton that should have sufficient space to accommodate this
additional labeling. FDA is aware that most of the currently marketed
products already include a consumer package insert. Therefore, to allow
firms greater flexibility, FDA is allowing some of the new information
to appear in the package insert. There are a limited number of products
currently marketed that will be affected by this final rule, and the
incremental one-time costs are minimal. The one-time costs include
designing the new carton, designing a new package insert, and the
inventory loss of any unused current labeling. FDA assumes the same
weighted average cost to relabel, inflated to reflect current dollars,
that it estimated for the final rule requiring uniform label formats of
OTC drug products (64 FR 13254 at 13279 to 13281) (i.e., $3,600 x
1.164[1] ($4,190) per stock keeping unit (SKU) (individual products,
packages, and sizes)). Inventory loss was estimated using data from a
study supporting the previously mentioned rule. With a 6-month
implementation period, inventory loss was estimated to be between $582
and $3,492 per SKU, depending on product sales, for an estimated
weighted average inventory loss of $2,386. The inventory loss and
redesign costs for the package insert are estimated to be about $1,606
per SKU[2].

FDA's Drug Listing System identifies 15 manufacturers and
distributors of OTC vaginal contraceptive and spermicide drug products
containing N9 that together produce approximately 40 SKUs. At a
relabeling cost of $4,190 per SKU and an inventory loss of $2,386 per
SKU, estimated total one-time cost of relabeling would be $263,040 (40
x ($4,190 + $2,386))[3]. Even if all required wording is revised on the
outer carton, manufacturers may revise their package inserts as well to
conform to the revised language. This adds another $64,240 (40 x
$1,606) to the one-time cost, for an estimated total of $327,280[4].

As FDA is providing the language of the labeling to be used, all
firms should have the necessary skills and personnel to perform the
required relabeling either in-house or by contractual arrangement. The
final rule does not require any new reporting or recordkeeping
activities. No additional professional skills are needed.

About 9 firms affected by this final rule meet the Small Business
Administration's definition of a small entity (fewer than 750
employees). The actual impact on these firms will vary depending on the
number and nature of the products they manufacture or distribute. All
nine entities market additional types of products and have only one or
two SKUs affected by this final rule. The average incremental cost per
SKU to comply with this final rule is estimated to be $8,182 ($327,280/
40 SKUs). Actual costs to the small entities will likely be lower
because distributors of low sales volume OTC drug products usually
market their products in packaging that costs less than the industry
average.

While the costs to individual manufacturers to relabel their
products are minimal, the potential benefits to consumers who use these
products are substantial. FDA considers it essential that users be
aware that these products do not protect against the AIDS virus (HIV)
or other STDs. The monetary benefit of potentially preventing any cases
of AIDS or STDs is significant compared to the minor cost of relabeling
these products to provide the new required information.

FDA considered but rejected several labeling alternatives: (1) A
shorter or longer implementation period, and (2) an exemption from
coverage for small entities. FDA considers it important that this
information appear in product labeling as soon as possible, but
acknowledges that implementation in a timeframe any less than 6 months
would be very difficult for affected manufacturers. However, because of
the importance of this new labeling information, FDA considers a period
of 12 months too long to implement this new labeling. FDA rejected an
exemption for small entities because the new labeling is also needed by
consumers who purchase products marketed by those entities.

The analysis shows that this final rule is not economically
significant under Executive Order 12866 and that FDA has considered the
burden to small entities. Based on this analysis, FDA does not believe
manufacturers will incur a significant economic impact. Therefore, FDA
certifies that the final rule will not have a significant economic
impact on a substantial number of small entities. No further analysis
is required under the Regulatory Flexibility Act (5 U.S.C. 605(b)).

V. Paperwork Reduction Act of 1995

FDA concludes that the labeling requirements in this document are
not subject to review by the Office of Management and Budget because
they do not constitute a "collection of information" under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the
labeling statements are a "public disclosure of information originally
supplied by the Federal government to the recipient for the purpose of
disclosure to the public" (5 CFR 1320.3(c)(2)).

VI. Environmental Impact

FDA has determined under 21 CFR 25.31(a) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VII. Federalism

FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
will have a preemptive effect on State law. Section 4(a) of the
Executive order requires agencies to "construe * * * a Federal statute
to preempt State law only where the statute contains an express preemption provision or there is some other clear evidence that the Congress intended preemption of State law, or where the exercise of
State authority conflicts with the exercise of Federal authority under
the Federal statute." Section 751 of the the act (21 U.S.C. 379r) is
an express preemption provision. Section 751(a) of the act (21 U.S.C.
379r(a)) provides that: "* * * no State or political subdivision of a
State may establish or continue in effect any requirement-- * * * (1)
that relates to the regulation of a drug that is not subject to the
requirements of section 503(b)(1) or 503(f)(1)(A); and (2) that is
different from or in addition to, or that is otherwise not identical
with, a requirement under this Act, the Poison Prevention Packaging Act
of 1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling
Act (15 U.S.C. 1451 et seq.)."

Currently, this provision operates to preempt States from imposing
requirements related to the regulation of nonprescription drug
products. (See section 751(b) through (e) of the act for the scope of
the express preemption provision, the exemption procedures, and the
exceptions to the provision.) This final rule would establish new
warning statements and other labeling for all OTC vaginal contraceptive
drug products. Although this final rule would have a preemptive effect,
in that it would preclude States from promulgating requirements related
to labeling for OTC vaginal contraceptive drug products that are
different from or in addition to, or not otherwise identical with a
requirement in the final rule, this preemptive effect is consistent
with what Congress set forth in section 751 of the act. Section 751(a)
of the act displaces both State legislative requirements and State
common law duties. We also note that even where the express preemption
provision is not applicable, implied preemption may arise. See Geier v.
American Honda Co., 529 US 861 (2000).

FDA believes that the preemptive effect of the final rule would be
consistent with Executive Order 13132. Section 4(e) of the Executive
order provides that "when an agency proposes to act through
adjudication or rulemaking to preempt State law, the agency shall
provide all affected State and local officials notice and an
opportunity for appropriate participation in the proceedings." FDA
provided the States with an opportunity for appropriate participation
in this rulemaking when it sought input from all stakeholders through
publication of the proposed rule in the Federal Register of January 16,
2003 (68 FR 2254). FDA received comments from three State groups on the
proposal and considered those comments in drafting this final rule.

In addition, on May 12, 2006, FDA's Division of Federal and State
Relations provided notice via fax and email transmission to elected
officials of State governments and their representatives of national
organization. The notice provided the States with further opportunity
for input on the rule. It advised the States of the publication of the
proposed rule and encouraged State and local governments to review the
notice and to provide any comments to the docket (Docket No. 1980N-0280
(formerly Docket No. 80N-0280)), opened in the January 16, 2003,
Federal Register proposed rule, by a date 30 days from the date of the
notice (i.e., by June 12, 2006), or to contact certain named
individuals. FDA received no comments in response to this notice. The
notice has been filed in the above numbered docket.

In conclusion, the agency believes that it has complied with all of
the applicable requirements under the Executive order and has
determined that the preemptive effects of this rule are consistent with
Executive Order 13132.

VIII. References

The following references are on display in the Division of Dockets
Management, 5630 Fishers Lane, rm 1061, Rockville, MD 20852, under
Docket No. 1980N-0280, and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.

(a) Studies indicate that use of vaginal contraceptive drug
products containing nonoxynol 9 does not protect against infection from
the human immunodeficiency virus (HIV), the virus that causes acquired
immunodeficiency syndrome (AIDS), or against the transmission of other
sexually transmitted diseases (STDs). Studies also indicate that use of
vaginal contraceptive drug products containing nonoxynol 9 can increase
vaginal irritation, such as the disruption of the vaginal epithelium,
and also can cause epithelial disruption when used in the rectum. These
effects may increase the risk of transmission of the AIDS virus (HIV)
from an infected partner. Therefore, consumers should be warned that
these products do not protect against the transmission of the AIDS
virus (HIV) or other STDs, that use of these products can increase
vaginal and rectal irritation, which may increase the risk of getting
the AIDS virus (HIV) from an HIV infected partner, and that the
products are not for rectal use. Consumers should also be warned that
these products should not be used by persons who have HIV/AIDS or are
at high risk for HIV/AIDS.

(b) The labeling of OTC vaginal contraceptive and spermicide drug
products containing nonoxynol 9 as the active ingredient, whether
subject to the ongoing OTC drug review or an approved drug application,
must contain the following warnings under the heading "Warnings," in
accordance with 21 CFR 201.66.

(1) "[bullet] For vaginal use only [bullet] Not for rectal (anal)
use" [both warnings in bold type].

(2) "Sexually transmitted diseases (STDs) alert [in bold type]:
This product does not [word "not" in bold type] protect against HIV/
AIDS or other STDs and may increase the risk of getting HIV from an
infected partner".

(3) "Do not use" [in bold type] if you or your sex partner has
HIV/AIDS. If you do not know if you or your sex partner is infected,
choose another form of birth control".

(4) "When using this product [in bold type] [optional, bullet] you
may get vaginal irritation (burning, itching, or a rash)".

(5) "Stop use and ask a doctor if [in bold type] [optional,
bullet] you or your partner get burning, itching, a rash, or other
irritation of the vagina or penis".

(c) The labeling of this product states under the "Other
information" section of the Drug Facts labeling in accordance with
Sec. 201.66(c)(7), "[bullet] when used correctly every time you have
sex, latex condoms greatly reduce, but do not eliminate, the risk of
catching or spreading HIV, the virus that causes AIDS.

(d) The labeling of this product includes the following statements
either on the outside container or wrapper of the retail package, under
the "Other information" section of the Drug Facts labeling in
accordance with Sec. 201.66(c)(7), or in a package insert:

(1) "[bullet] studies have raised safety concerns that products
containing the spermicide nonoxynol 9 can irritate the vagina and
rectum. Sometimes this irritation has no symptoms. This irritation may
increase the risk of getting HIV/AIDS from an infected partner".

(2) "[bullet] you can use nonoxynol 9 for birth control with or
without a diaphragm or condom if you have sex with only one partner who
is not infected with HIV and who has no other sexual partners or HIV
risk factors".

(3) "[bullet] use a latex condom without nonoxynol 9 if you or
your sex partner has HIV/AIDS, multiple sex partners, or other HIV risk
factors".

(4) "[bullet] ask a health professional if you have questions
about your best birth control and STD prevention methods".

(e) Any drug product subject to this section that is not labeled as
required and that is initially introduced or initially delivered for
introduction into interstate commerce after June 19, 2008, is
misbranded under section 502 of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 352), is a new drug under section 505 of the
act (21 U.S.C. 355), and is subject to regulatory action.